Androgen which is one kind of steroid hormones is secreted from the testis and adrenal cortex and causes an androgenic hormone action. Androgen is taken in a target cell to act on an androgen receptor and the receptor combined with androgen forms a dimer. Then, the dimer binds to an androgen-response-element on a DNA to accelerate synthesis of an m-RNA and to induce proteins which direct androgenic actions, whereby various actions are expressed in vivo (Prostate Suppl., 6, 1996, 45-51, Trends in Endocrinology and Metabolism, 1998 9(8), 317-324).
Diseases in which androgen acts as an aggravating factor include prostate cancer, benign prostatic hyperplasia, virilism, hirsutism, baldness, acne, seborrhea, and the like. Therefore, antiandrogenic agents have been employed for treating these diseases which may be attributed to androgen.
Antiandrogenic agents, which have substrate resembling steroidal structure or non-steroidal structure are currently used in the clinical field. Though chlormadinone acetate and the like are known as the steroidal antiandrogen, it is known that, since separation of actions of these compounds from other steroids having similar structures is not sufficient, they cause changes in the blood hormone level and induces serious side effects such as reduction of libido and the like (Jpn. J. Clin. Oncol., 1993, 23(3), 178-185).
On the other hand, as the compounds each having a non-steroidal structure, acylanilide derivatives such as flutamide (Patent Document 1) and bicalutamide (Patent Literatures 2 and 3) are known but these compounds are not sufficient in antiandrogenic action. Therefore, in the treatment of prostate cancer, combination therapy with an LH-RH agonist is generally adopted (Non-Patent Document 1).
The compounds of the present invention are compounds which fall within the range of the following general formula defined in Claims of Patent Document 4:
for the symbols in the formula, refer to Patent Document 4, and have the same pharmacological action but the compounds in present invention are not disclosed or suggested as specific examples in the above Document. The compounds having the most strong activity described in the above Document have problems of agonistic action, body weight loss, and the like other than the main effect. Also, the compound in the above Document having no these side effects and having a strong activity exhibits a low oral activity. Thus, it has been desired to develop a pharmaceutical agent which further improves these points.[Patent Document 1]
JP-A-49-81332
[Patent Document 2]
GB 8221421
[Patent Document 3]
International Publication WO 95/19770 Pamphlet
[Patent Document 4]
International Publication WO 00/17163 Pamphlet
[Non-Patent Document 1]
Nihon Rinsho 1998, 56(8), 2124-2128